The present invention relates to a new process by enzymic reaction for producing a carboxylic acid ester. More particularly, the present invention relates to a process for producing a carboxylic acid ester which comprises reacting a hydroxy compound with a carboxylic anhydride in the presence of carboxyl esterase as a catalyst in an organic solvent.
Hitherto, synthetic reactions using organic chemical procedures and enzymic reactions have been used for producing a carboxylic acid ester.
As the synthetic reactions using organic chemical procedures, for example, esterification, such as the dehydration reaction of the following equation: ##STR1## wherein a hydroxy compound is an acyl group acceptor and a carboxylic acid is an acyl group donor, and transesterification of the following equation: ##STR2## wherein a hydroxy compound is an acyl group acceptor and an ester compound is an acyl group donor have been known.
As for the enzymic reaction, esterification, i.e. reverse hydrolysis where a hydroxy compound and a carboxylic acid are used as a substrate, and transesterification where a hydroxy compound and an ester compound are used as a substrate have been known.
However, when the hydroxy compound contains two or more hydroxy groups, one or more of the hydroxy groups can not selectively and specifically be converted into acyloxy group(s) by the synthetic reaction using organic chemical procedures.
For example, in the case that lankacidin A, i.e. a compound of the formula: ##STR3## [This compound is effective as an antibacterial agent and antibiotic, e.g. antibiotic against swine dysentery infections (c.f. U.S. Pat. No. 3,676,300; and U.S. Pat. No. 4,480,033)] is produced from lankacidin C, i.e. a compound of the formula: ##STR4## which has two hydroxy substituents at the 8- and 14-positions, a hydroxy group at the 14-position can not selectively and specifically be converted into an acyloxy group by the synthetic reaction.
Accordingly, for the purpose of converting hydroxy group(s) selectively and specifically into acyloxy group(s), the synthetic reaction using organic chemical procedures is not effective.
The enzymic reaction using a hydroxy compound and a carboxylic acid or ester compound as the substrate makes it possible to convert hydroxy group(s) selectively and specifically into acyloxy group(s) (c.f. U.S. Pat. No. 3,676,300 and U.S. Pat. No. 4,480,033).
However, in these enzymic reactions, a large amount of the substrate, such as a carboxylic acid or an ester compound is necessary, because the enzymes catalyze the chemical reaction in both forward and backward directions mainly depending upon the concentrations of substrates involved. Besides, the yield of the objective ester compound is very low.
Furthermore, in the esterification by enzymic reaction using a hydroxy compound and a carboxylic acid, the reaction must be conducted under completely anhydrous conditions. In the transesterification by enzymic reaction using a hydroxy compound and an ester compound, an ester compound as an acyl group donor often undergoes hydrolysis by carboxyl esterase catalyst, and hydolysis of the formed ester compound proceeds by carboxyl esterase at the same time. This makes it necessary to use a large excess of an ester compound (the substrate) as acyl group donor.
Besides, it is difficult to completely convert hydroxy group(s) into acyloxy group(s), because the transesterification by enzymic reaction is reversible by nature.
The present inventors studied the enzymic reaction to selectively and specifically convert hydroxy group(s) into acyloxy group(s) in high yield from a small amount of an acyl group donor.
As a result, the present inventors have found that in the enzymic reaction, the yield as well as quality of the objective ester compounds can remarkably be improved by employing a carboxylic anhydride as an acyl group donor in an organic solvent.
These findings were followed by continued studies, which have culminated in the present invention.